Influenza A viruses (IAV) are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have resulted in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S., and 40 million people worldwide. Pandemics in 1957 and 1968, while less severe, were also of major public health importance. A novel influenza A virus of swine origin became pandemic in 2009, causing the first pandemic in 41 years. In addition, annual epidemic influenza causes are also very significant resulting in up to 49,000 deaths in the US annually. Highly pathogenic avian H5N1 viruses continue to circulate enzootically in poultry in many countries and continue to cause human infections. Recently a novel avian H7N9 strain emerged in China also causing human infections and fatalities. A variety of experimental pathogenesis studies to model host adaptation, map viral virulence factors and host factors in disease progression, evaluate novel therapeutics and vaccines were performed. Understanding the origin, virulence, and pathogenic properties of the 1918 virus, is crucial for current public health preparedness and future pandemic planning. The origin of the 1918 pandemic virus has not been resolved, but its coding sequences are very like those of avian influenza virus. Recent work with 1918:low pathogenicity avian influenza H1N1 chimeric viruses suggested that the virulence factor(s) in the 1918 hemagglutinin (HA) gene might be shared with low pathogenicity avian influenza viruses expressing H1 HAs. Zoonotic avian influenza virus infections may lead to epidemics or pandemics. The 1918 pandemic influenza virus has an avian influenza virus-like genome, and its H1 hemagglutinin was identified as a key mammalian virulence factor. A chimeric 1918 virus expressing a contemporary avian H1 hemagglutinin, however, displayed murine pathogenicity indistinguishable from that of the 1918 virus. Here, isogenic chimeric avian influenza viruses were constructed on an avian influenza virus backbone, differing only by hemagglutinin subtype expressed. Viruses expressing the avian H1, H6, H7, H10, and H15 subtypes were pathogenic in mice and cytopathic in normal human bronchial epithelial cells, in contrast to H2-, H3-, H5-, H9-, H11-, H13-, H14-, and H16-expressing viruses. Mouse pathogenicity was associated with pulmonary macrophage and neutrophil recruitment. These data suggest that avian influenza virus hemagglutinins H1, H6, H7, H10, and H15 contain inherent mammalian virulence factors and likely share a key virulence property of the 1918 virus. Consequently, zoonotic infections with avian influenza viruses bearing one of these hemagglutinins may cause enhanced disease in mammals. Pneumonia due to viral and bacterial infections is a leading cause of death in children and adults worldwide. Severe influenza and bacterial co-infection induce hypoxic respiratory failure, manifested as acute respiratory distress syndrome. Pre-clinical studies of pneumonia in animals that evaluate pathogenesis and treatment do not capture the evolution of oxygen gas exchange abnormalities that can be correlated with the development and resolution of lung injury in humans. To address this a model of infection-induced lung injury in Rhesus Macaques was developed and it was demonstrated that oxygen gas exchange abnormalities correlated with radiologic, immunologic, and pathologic markers of disease. Animals were infected with influenza A virus via intratracheal or small-particle aerosol inoculation, methicillin-resistant Staphylococcus aureus via intratracheal inoculation, or connected with influenza (intra-tracheal or aerosol) and methicillin-resistant Staphylococcus aureus combined. We observed that intratracheal delivered influenza A virus alone or in combination with methicillin-resistant Staphylococcus aureus induced acute lung injury. Oxygen gas exchange abnormalities correlated well with radiologic and pathologic abnormalities as well as cellular immune responses in lung-lining fluid. Methicillin-resistant Staphylococcus aureus alone and aerosol influenza infection in combination with methicillin-resistant Staphylococcus aureus induced pneumonia without significant oxygen gas exchange abnormalities. This model provides a new tool for correlating impaired oxygenation with radiologic and biologic markers of disease to advance understanding and treatment of severe pneumonia. Influenza virus infections are a global public health problem, with a significant impact of morbidity and mortality from both annual epidemics and pandemics. The current strategy for preventing annual influenza is to develop a new vaccine each year against specific circulating virus strains. Because these vaccines are unlikely to protect against an antigenically divergent strain or a new pandemic virus with a novel hemagglutinin (HA) subtype, there is a critical need for vaccines that protect against all influenza A viruses, a so-called universal vaccine. Here we show that mice were broadly protected against challenge with a wide variety of lethal influenza A virus infections (94% aggregate survival following vaccination) with a virus-like particle (VLP) vaccine cocktail. The vaccine consisted of a mixture of VLPs individually displaying H1, H3, H5, or H7 HAs, and vaccinated mice showed significant protection following challenge with influenza viruses expressing 1918 H1, 1957 H2, and avian H5, H6, H7, H10, and H11 hemagglutinin subtypes. These experiments suggest a promising and practical strategy for developing a broadly protective universal influenza vaccine.